Unstructured loop of Talin’s FERM domain can serve as a flexible membrane anchor

This allows for interaction with PIP₂ even in Talin’s autoinhibited form and paves the way to establish known binding surfaces.

Follow the QR code or visit https://github.com/hits-mbm-dev/paper-talin-loop for the repository of the paper draft. Or even better yet, talk to me in front of the poster!

Abstract

Figure 1: The autoinhibited (Cryo-EM) structure of Talin1 found by Dedden et al. (2019) aligned with the structure of the FERM domain by Elliott et al. (2010) and the modelled flexible loop in F1 (darker cyan)

Focal adhesions mediate the interaction of the cytoskeleton with the extracellular matrix (ECM). Talin is a central regulator and adaptorprotein of the multiprotein focal adhesion complexes and is responsible for integrin activation and force-sensing. We evaluated direct interactions of talin with the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP₂) by means of molecular dynamics simulations. A newly published autoinhibitory structure of talin, where common PIP₂ interaction sites are covered up, sparked our curiosity for a hitherto less examined loop as a potential site of first contact. We show that this unstructured loop in the F1 subdomain of the talin1 FERM domain is able to interact with PIP₂ and can facilitate further interactions by serving as a flexible membrane anchor.

Figure 2: A rotational sampling of the F0F1 domain reaveals the strong propensity of the F1 loop to interact with the membrane. Even in the most unfavorable position, the loop still has a high probability to find the membrane and interact with PIP₂ due to the large search space it can cover.

Figure 3: The residues of F0F1 interacting with PIP₂ are highlighted in blue, with their CA-atoms labelled

Figure 5: Once contact has been established via the loop, simulations with the full lenght FERM domain show that known PIP₂ interaction sites are recovered. The location of binding surfaces found by Chinthalapudi, Rangarajan, and Izard (2018) are highlighted with red lines on the schematic: K272 of F2 and K316, K324, E342, and K343 of F3.

Acknowledgments

This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No. 101002812)

This poster was made betterposter (Aden-Buie 2022) R package and quarto (Allaire et al. 2022).

References

Aden-Buie, Garrick. 2022. Betterposter: A Better Scientific Poster. Manual.

Allaire, J. J., Charles Teague, Carlos Scheidegger, Yihui Xie, and Christophe Dervieux. 2022. “Quarto.” https://doi.org/10.5281/zenodo.5960048.

Chinthalapudi, Krishna, Erumbi S. Rangarajan, and Tina Izard. 2018. “The Interaction of Talin with the Cell Membrane Is Essential for Integrin Activation and Focal Adhesion Formation.” Proceedings of the National Academy of Sciences of the United States of America 115 (41): 10339–44. https://doi.org/10.1073/pnas.1806275115.

Dedden, Dirk, Stephanie Schumacher, Charlotte F. Kelley, Martin Zacharias, Christian Biertümpfel, Reinhard Fässler, and Naoko Mizuno. 2019. “The Architecture of Talin1 Reveals an Autoinhibition Mechanism.” Cell 179 (1): 120–131.e13. https://doi.org/10.1016/j.cell.2019.08.034.

Elliott, Paul R., Benjamin T. Goult, Petra M. Kopp, Neil Bate, J. Günter Grossmann, Gordon C. K. Roberts, David R. Critchley, and Igor L. Barsukov. 2010. “The Structure of the Talin Head Reveals a Novel Extended Conformation of the FERM Domain.” Structure(London, England:1993) 18 (10-13): 1289–99. https://doi.org/10.1016/j.str.2010.07.011.

Intrinsically disordered region of talin’s FERM domain functions as an initial PIP2 recognition site

Unstructured loop of Talin’s FERM domain can serve as a flexible membrane anchor

Abstract

Acknowledgments

References